Project Summary/Abstract: Chronic, neuropathic pain is 1 of the most important unmet medical needs in the United States, affecting tens to hundreds of millions of people nationwide at some time during their lives. Novel therapeutic approaches are desperately needed. The brain peptides neurotensin (NT) and its fully active derivative NT[8-13] have been shown to exhibit considerable, long-term analgesic activity, however the compounds are unable to be delivered across the blood brain barrier. In previous efforts, we have engineered a compound, ABS201, that possesses significant antipsychotic potential when orally administered; recently, we have demonstrated using an appropriate rat model of neuropathic pain that it also has dramatic analgesic activity. These activities are mediated through the compound's activity as an agonist of neurotensin receptor-(NTR-1) and NTR-2, respectively. While ABS201 has considerable promise for development as an analgesic, we hypothesize that further rational design will enable identification of a derivative in which NTR-2/NTR-1 receptor selectivity can be increased such that the antipsychotic activity is minimized or eliminated. 3 Specific Aims will be completed to address the hypothesis. In Specific Aim 1, a set of 10 derivatives of ABS 201 will be synthesized that are designed to improve selectivity of the compound for NTR-2 over NTR-1 and thus retaining analgesic activity. These compounds (as well as ABS201) will be evaluated in Specific Aim 2 for analgesic activity in 3 rat models, the tail flick, hotplate and formalin assays for chronic pain. Both IP and oral dosing will be performed for all compounds. In Specific Aim 3, other potential discriminators, including NTR-2 and NTR-1 binding, serum stability and functional agonism will be evaluated. From the results of these studies, a lead will be identified for advancement into Phase 2 of this project, which will include further evaluation of the compound's efficacy, potential for toxicity and pharmacokinetic characterization appropriate for submission of an IND. Specific Aim 1 will be completed at Argolyn Bioscience while Specific Aims 2 and 3 will be completed under a subcontract at the Medical University of South Carolina. Project Narrative: Chronic, neuropathic pain is 1 of the most important unmet medical needs. An orally active derivative of the brain peptide neurotensin has been identified that exhibits potent analgesic activity in rats equivalent to morphine but with a unique mechanism of activity. This compound has the potential for development as a novel therapeutic agent for chronic pain. [unreadable] [unreadable] [unreadable]